Biological buffers with wide buffering ranges

ABSTRACT

Amines and amine derivatives that improve the buffering range, and/or reduce the chelation and other negative interactions of the buffer and the system to be buffered. The reaction of amines or polyamines with various molecules to form polyamines with differing pKa&#39;s will extend the buffering range, derivatives that result in polyamines that have the same pKa yields a greater buffering capacity. Derivatives that result in zwitterionic buffers improve yield by allowing a greater range of stability.

This is a continuation of U.S. application Ser. No. 15/649,869 filedJul. 14, 2017 and other previous parent applications claimed in theApplication Data Sheet. U.S. application Ser. No. 15/649,869 is herebyincorporated by reference in its entirety.

BACKGROUND Field of the Invention

The present invention relates generally to the field of amines and moreparticularly to a classes of amines used as buffers in biologicalsystems.

Description of the Problem Solved by the Invention

Amines are very useful compounds in the buffering of biological systems.Each class of amine has various limitations which require choosing anamine based on multiple factors to select the best amine. For example,pH buffering range is typically most important, but issues of chelation,and pH range stability, and solubility also come into play. Typically, asuboptimal buffer will result in yields that are well below thepotential yield. The invention disclosed improves the yields infermentation and purification, and improves shelf stability of proteinsand amino acids.

SUMMARY OF THE INVENTION

The present invention relates to amines and amine derivatives thatimprove the buffering range, and/or reduce the chelation and othernegative interactions of the buffer and the system to be buffered. Thereaction of amines or polyamines with various molecules to formpolyamines with differing pKa's will extend the buffering range,derivatives that result in polyamines that have the same pKa yields agreater buffering capacity. Derivatives that result in zwitterionicbuffers improve yield by allowing a greater range of stability.

DESCRIPTION OF THE FIGURES

Attention is now directed to the following figures that describeembodiments of the present invention:

FIG. 1 shows the derivation of polyamines and zwitterionic buffers fromtromethamine.

FIG. 2 shows the derivation of zwitterionic buffers and polyamines fromaminomethylpropanol.

FIG. 3 shows the reaction of 2-methyl-2-nitro-1-propanol withacrylonitrile and its derivatives.

FIG. 4 shows the reaction of 2-nitro-2-ethyl-1,3-propanediol withacrylonitrile and its derivatives where x, y, and n are all integerswhere x and y are chosen independently, such that x+y=n and n is greaterthan zero.

FIG. 5 shows the reaction of 2-nitro-2-methyl-1,3-propanediol withacrylonitrile and its derivatives where x, y, and n are all integerswhere x and y are chosen independently, such that x+y=n and n is greaterthan zero.

FIG. 6 shows the reaction of tris(hydroxymethyl)nitromethane withacrylonitrile and its derivatives where x, y, z, and n are all integerswhere x, y and z are chosen independently, such that x+y+z=n and n isgreater than zero.

FIG. 7 shows the reaction of 2-nitro-1,3-propanediol with acrylonitrileand its derivatives where x, y, and n are all integers where x and y arechosen independently, such that x+y=n and n is greater than zero.

FIG. 8 shows the reaction of 2-nitro-1-butanol with acrylonitrile andits derivatives.

FIG. 9 shows FIG. 9 shows alkoxylation of aminomethylpropanol.

FIG. 10A shows the synthesis of a very mild, high foaming, surfactantderived from MCA.

FIG. 10B shows the synthesis of a very mild, high foaming, surfactantderived from SVS.

FIG. 11 shows the synthesis of a series of buffers with 2-nitropropaneas the starting material.

FIG. 12 shows FIG. 12 shows the synthesis of a series of buffers with1-nitropropane as a starting material where n and m are integers wherem+n is greater than zero and n is greater than or equal to m.

FIG. 13 shows the synthesis of a series of buffers with nitroethane as astarting material where n and m are integers where m+n is greater thanzero and n is greater than or equal to m.

FIG. 14 shows the synthesis of a series of buffers with nitromethane asa starting material where x, y, z and n are integers and x+y+z=n and nis greater than zero.

FIG. 15 shows the synthesis of a series of zwitterionic buffers based onacrylic acids.

FIG. 16 shows the synthesis of a zwitterionic sulfonate based ontromethamine.

FIG. 17 shows the synthesis of a zwitterionic sulfonate based onaminomethylpropanol.

FIG. 18-25 show the synthesis of families of zwitterionic buffers fromnitroalcohols.

FIG. 26 shows the synthesis of zwitterionic buffers from morpholine.

FIG. 27 shows the synthesis of zwitterionic buffers from hydroxyethylpiperazine.

FIG. 28 shows the synthesis of zwitterionic buffers from piperazine.

FIG. 29 shows the synthesis of zwitterionic buffers from ethyleneamines.

FIG. 30 shows the synthesis of a zwitterionic buffer with primary,secondary, tertiary, or quaternary amine functionality.

FIGS. 31-33 show the synthesis of mild zwitterionic surfactants fromnitroalcohols.

FIG. 34-37 show the synthesis of polyamines from nitroalcohols.

FIG. 38 shows the synthesis of diamines from nitroalcohols andaminoalcohols.

FIG. 39 shows the synthesis of isopropyl amine acrylate buffers and mildsurfactants.

FIG. 40 shows the synthesis of zwitterionic buffers from SVS and MCAderived from isopropyl amine as well as mild surfactants and diamines.

FIG. 41 shows the synthesis of a sultaine zwittterionic buffer ofisopropyl amine.

FIG. 42 shows the synthesis of zwitterionic buffers from amino alcoholsand itaconic acid.

FIG. 43 shows the synthesis of nitro acids from nitroalcohols anditaconic acid.

FIG. 44 shows the synthesis of primary amino zwitterionic buffers fromnitro acids.

FIG. 45. shows the synthesis of a family of zwitterionic buffers fromitaconic acid and amines.

FIG. 46 shows the synthesis of surfactants from amines and itaconic acidintermediates.

FIG. 47 shows the synthesis of nitroacids from nitroparaffins anditaconic acid.

FIG. 48 shows the synthesis of zwitterionic buffers from nitro acids.

FIG. 49 shows the synthesis of zwitterionic buffers from4-aminopyridine.

FIG. 50 shows the synthesis zwitterionic buffers from the ketimineconformation of 4-aminopyridine.

FIG. 51 shows the synthesis of zwiiterionic sultaines from4-aminopyridine.

FIG. 52 shows the synthesis of zwitterionic buffers from taurine.

FIG. 53 shows the synthesis of zwitterionic buffers from homotaurine.

FIG. 54 shows the synthesis of zwitterionic buffers from aspartic acid.

FIG. 55 shows the synthesis of sultaine zwitterionic buffers from sodiumbisulfite and epichlorohydrin.

FIG. 56 shows the synthesis of sultaine zwitterionic buffers from sodiumbisulfite, epichlorohydrin, and aminoalcohols.

FIG. 57 shows the synthesis of zwitterionic buffers from propane sultone

FIG. 58 shows the synthesis of amidoamine buffers from acrylamide.

FIG. 59 shows the syntheis of amidoamine buffers from methacrylamide.

FIG. 60 shows the synthesis of amidoamine buffers from taurines anddiamines.

FIG. 61 shows the synthesis of zwitterionic amidoamine buffers frompropone sultone and SVS.

FIG. 62 shows the synthesis of sultaine amidoamine zwitterionic buffers.

FIG. 63 shows the synthesis of a family of compounds as zwitterionicbuffers and products that are expected to be useful as multiplesclerosis and spinal cord injury therapies.

FIG. 64 shows amide based zwitterionic buffers and products that areexpected to be useful as multiple sclerosis and spinal cord injurytherapies.

FIG. 65 shows additional zwitterionic buffers based on 4-aminopyridineamides. These products are also expected to be useful as multiplesclerosis and spinal cord injury therapies.

FIG. 66 shows the synthesis of zwitterionic buffers that are alsoexpected to be useful as multiple sclerosis and spinal cord injurytherapies. Most of this family has increased hydrogen bonding and isbased on the MCA derived zwitterionic buffers disclosed herein.

FIG. 67 shows the synthesis of zwitterionic buffers that are alsoexpected to be useful as multiple sclerosis and spinal cord injurytherapies. Most of this family has increased hydrogen bonding and isbased on the acrylic acid derived zwitterionic buffers disclosed herein.

FIG. 68 shows the synthesis of zwitterionic buffers that are alsoexpected to be useful as multiple sclerosis and spinal cord injurytherapies. Most of this family has increased hydrogen bonding and isbased on the methacrylic acid derived zwitterionic buffers disclosedherein.

FIG. 69 shows the synthesis of zwitterionic buffers that are alsoexpected to be useful as multiple sclerosis and spinal cord injurytherapies. Derived from ethylene amines.

FIG. 70 shows the synthesis of amidoamine buffers that are steariclyhindered.

FIG. 71 shows the synthesis of amidoamine buffers that are steariclyhindered with extensive hydrogen bonding.

FIG. 72 shows the synthesis of amidoamine buffers.

FIG. 73 shows that any of the amidoamine buffers taught herein, maybereduced to aminoalcohols or diamines.

FIG. 74 shows the esterification of the zwitterionic buffers.

FIG. 75 shows the esterification, mono- and diesterification of theitaconic acid based zwitterionics.

FIG. 76 shows the synthesis of diacid, tertiary amine, zwitterionicbuffers.

FIG. 77 shows the synthesis of amido amines from zwitterionic buffers,where A, D, and E are independently chosen from, —H, —CH3, —CH2CH3,—CH2OH. G is chosen from —H, —CH3, —CH2CH3, —OH. R and R′ are chosenindependently from the group alkyl, alkenal, or alkynal, linear orbranched, saturated or unsaturated. Additionally, R′ may be H.

FIG. 78 shows the synthesis of a variety of 4-aminopyridine derivativesthat are useful buffers.

FIG. 79 shows the condensation polymerization of the hydroxyl functionalzwitterionics.

FIG. 80 clarifies the amidoamine to aminoalcohol or diamine synthesisoriginally outlined in FIG. 73.

FIG. 81-84 teach the synthesis of sulfonamides from the zwitterionicbuffers.

FIG. 85 shows the synthesis of quaternary amine salts from tertiaryaminoalcohols where A, D, and E are independently chosen from, —H, —CH3,—CH2CH3, —CH2OH. R and R′ are chosen independently and selected from thegroup alkyl, alkenal, or alkynal, linear or branched, saturated orunsaturated.

FIG. 86-87 teach the synthesis of sulfonate esters of the zwitterionicbuffers.

FIG. 88-89 teach the synthesis of amino acid, zwitterionic buffers withprimary amine functionality.

FIG. 90 expands on the quaternary amine salts shown in FIG. 85 where A,D, and E are independently chosen from, —H, —CH3, —CH2CH3, —CH2OH. G ischosen from —H, —CH3, —CH2CH3, —OH. R and R′ are chosen independentlyand selected from the group alkyl, alkenal, or alkynal, linear orbranched, saturated or unsaturated. L, M, Q, X, Z are independentlychosen from the group —H, —OH, —CH2OH, alkyl, alkenal, or alkynal,linear or branched, saturated or unsaturated.

FIGS. 91-92 show the use of acrylate hydroxyesters in the synthesis ofbiological buffers.

FIG. 93 teaches the synthesis of a family of phosphonates andphosphonate amino acids.

FIG. 94 teaches the synthesis of a family of phosphamides.

FIG. 95 teaches the synethsis of zwitterionic buffers based on MCA andsulfonic acids.

FIG. 96 teaches the synthesis of an enzyme inhibitor.

FIG. 97 teaches the synthesis of diacid sulfonic acid buffers.

FIG. 98 teaches diacid buffers with sulfonic acid and phosphonatefunctionality.

FIG. 99 teaches diacid buffers with sultaine and carboxcylic acidfunctionality.

FIG. 100-101 teach the reduction of the zwitterionic buffers to alcoholsand ethers.

FIG. 102-104 teaches the synthesis of zwitterionic buffers and theirreduction to alcohols and ethers.

FIG. 105 teaches the synthesis of sulfonamide buffers.

FIG. 106 teaches the synthesis of mono and disubtituted Michaeladditions to form zwitterionic buffers.

FIG. 107 teaches the synthesis of a new class of amines andaminoalcohols and their derivatives where A and D are independentlychosen from —H, —CH3, —CH2CH3, —CH2CH2CH3, —CH2OH, —CH2COOH,—CH2CH2COOH, —CH2CH(CH3)COOH, —CH2PO(OH)2. E is alkyl, saturated orunsaturated, branched or linear with from 2-22 carbons. G is chosen from—H, —CH3, —CH2CH3, —OH. J is chosen from alkyl, alkenyl, alkynyl,branched or linear, —H, —(CH2CH2O)nH, —(CH2CH2CH2O)nH, —(CH2CH(CH3)O)nH,—(CH2C(CH3)2O)nH. R, R′, R″, R′″ are independently chosen from, alkyl,alkenyl, alkynyl, branched or linear. n and m are integers, both may notbe zero.

FIG. 108 teaches the synthesis of a new class of amines andaminoalcohols and derivatives of nitro compounds and valeraldehyde. Aand D are independently chosen from —H, —CH3, —CH2CH3, —CH2CH2CH3,—CH2OH, —CH2COOH, —CH2CH2COOH, —CH2CH(CH3)COOH, —CH2PO(OH)2. G is chosenfrom —H, —CH3, —CH2CH3, —OH. J is chosen from alkyl, alkenyl, alkynyl,branched or linear, —H, —(CH2CH2O)nH, —(CH2CH2CH2O)nH, —(CH2CH(CH3)O)nH,—(CH2C(CH3)2O)nH. R, R′, R″, R′″ are independently chosen from, alkyl,alkenyl, alkynyl, branched or linear. n and m are integers, both may notbe zero.

FIG. 109 teaches the synthesis of a new class of aminoalcohols and theirderivatives based on monosubtitution of gluteraldehyde and nitrocompounds. Where A and D are independently chosen from —H, —CH3,—CH2CH3, —CH2CH2CH3, —CH2OH, —CH2COOH, —CH2CH2COOH, —CH2CH(CH3)COOH,—CH2PO(OH)2. G is chosen from —H, —CH3, —CH2CH3, —OH. J is chosen fromalkyl, alkenyl, alkynyl, branched or linear, —H, —(CH2CH2O)nH,—(CH2CH2CH2O)nH, —(CH2CH(CH3)O)nH, —(CH2C(CH3)2O)nH. R, R′, R″, R′″ areindependently chosen from, alkyl, alkenyl, alkynyl, branched or linear.n and m are integers, both may not be zero.

FIG. 110 teaches the synthesis of diamines and their derivatives basedon gluteraldehyde and nitro compounds where A and D are independentlychosen from —H, —CH3, —CH2CH3, —CH2CH2CH3, —CH2OH, —CH2COOH,—CH2CH2COOH, —CH2CH(CH3)COOH, —CH2PO(OH)2. G is chosen from —H, —CH3,—CH2CH3, —OH. J is chosen from alkyl, alkenyl, alkynyl, branched orlinear, —H, —(CH2CH2O)nH, —(CH2CH2CH2O)nH, —(CH2CH(CH3)O)nH,—(CH2C(CH3)2O)nH.

FIG. 111 teaches the synthesis of diamines and their derivatives basedon gluteraldehyde and nitro compounds where A and D are independentlychosen from —H, —CH3, —CH2CH3, —CH2CH2CH3, —CH2OH, —CH2COOH,—CH2CH2COOH, —CH2CH(CH3)COOH, —CH2PO(OH)2. G is chosen from —H, —CH3,—CH2CH3, —OH. R, R′, R″, R′″ are independently chosen from, alkyl,alkenyl, alkynyl, branched or linear. n and m are integers, both may notbe zero.

FIG. 112 teaches the synthesis of a class of amino alcohols derived fromglucose and nitro compounds and their derivatives where A and D areindependently chosen from —H, —CH3, —CH2CH3, —CH2CH2CH3, —CH2OH,—CH2COOH, —CH2CH2COOH, —CH2CH(CH3)COOH, —CH2PO(OH)2. G is chosen from—H, —CH3, —CH2CH3, —OH. J is chosen from alkyl, alkenyl, alkynyl,branched or linear, —H, —(CH2CH2O)nH, —(CH2CH2CH2O)nH, —(CH2CH(CH3)O)nH,—(CH2C(CH3)2O)nH. n is an integer.

FIG. 113 teaches the synthesis of a class of amino alcohols derived fromglucose and nitro compounds and their derivatives.

FIG. 114-115 teach the synthesis of banzaldehyde and nitro compounds andtheir derivatives.

FIG. 116 teaches how dimmers can be formed when using a nitro compoundwith more than one hydrogen on the nitro containing carbon.

FIG. 117 teaches how dialdehydes can be used to make dimmers andpolymers.

FIG. 118 teaches a novel route to nitro acids and primary amino acids ofseveral types where A and D are independently chosen from —H, —CH3,—CH2CH3, —CH2CH2CH3, —CH2OH. E is alkyl, saturated or unsaturated,branched or linear with from 2-22 carbons. G is chosen from —H, —CH3,—CH2CH3, —OH. J is chosen from alkyl, alkenyl, alkynyl, branched orlinear, —H, —(CH2CH2O)nH, —(CH2CH2CH2O)nH, —(CH2CH(CH3)O)nH,—(CH2C(CH3)2O)nH.

FIG. 119 teaches the synthesis of surfactants based on aldehydes andnitro compounds where A is chosen from —H, —CH3, —CH2CH3, —CH2CH2CH3,—CH2OH, —CH2COOH, —CH2CH2COOH, —CH2CH(CH3)COOH, —CH2PO(OH)2. E is alkyl,saturated or unsaturated, branched or linear with from 1-22 carbons. Gis chosen from —H, —CH3, —CH2CH3, —OH. J is chosen from alkyl, alkenyl,alkynyl, branched or linear, —H, —(CH2CH2O)nH, —(CH2CH2CH2O)nH,—(CH2CH(CH3)O)nH, —(CH2C(CH3)2O)nH. n is an integer.

FIG. 120 expands FIG. 107 to cover an additional species where thealdehyde is acetaldehyde in which E —CH₃. A and D are independentlychosen from —H, —CH3, —CH2CH3, —CH2CH2CH3, —CH2OH, —CH₂COOH,—CH₂CH₂COOH, —CH₂CH(CH₃)COOH, —CH₂PO(OH)₂, —CH₂CH₂CH₂CN, E is alkyl,saturated or unsaturated, branched or linear with from 1-22 carbons. Gis chosen from —H, —CH3, —CH2CH3, —OH. J is chosen from alkyl, alkenyl,alkynyl, branched or linear, —H, —(CH₂CH₂O)_(n)H, —(CH₂CH₂CH₂O)_(n)H,—(CH₂CH(CH₃)O)_(n)H, —(CH₂C(CH₃)₂O)_(n)H. R, R′, R″, R′″ areindependently chosen from, alkyl, alkenyl, alkynyl, branched or linear.n and m are integers, both may not be zero.

FIG. 121 expands upon the zwitterionic buffers based on 4-aminopyridineto include 2 and 3-aminopyridine to make zwitterionic phosphonate, aminoacid buffers, and amides. It builds upon the zwitterionic buffers inteaching a class of pyridine functional monomers, polymers, oligamers,and prepolymers. Where n is 1 or 2. A, G, and E, is chosen from N or C.R, R1 and J are independently chosen from alkyl, saturated orunsaturated, branched or linear, from 1 to 22 carbons, —H, —CH2OH,—CH2CH2OH, —C(Q)(Q′)(Q″) where Q,Q′, and Q″ are independently chosenfrom —H, —CH3, —CH2CH3, —CH2OH, L is chosen from —H, —CH3, —CH2CH3, —OH.L is chosen from —H, —CH3, —CH2CH3, —CH2OH. n′ is the standard repeatingunit of a polymer, dimer or oligamer.

FIGS. 122-123 expand upon the zwitterionic buffers based on4-aminopyridine to include 2 and 3-aminopyridine to make zwitterionicphosphonate, amino acid buffers, and amides. It builds upon thezwitterionic buffers in teaching a class of pyridine functionalmonomers, polymers, oligamers, and prepolymers.

FIG. 124 expands the work with 4-Aminopyridine to include2-aminopryidine and 3-aminopyridine, as well as introduces sulfamidesthat act as channel blockers and antibiotics. Where n is 1 or 2. A, A′,G, G′, E and E′, is chosen from N or C. m is an integer from 1 to 6. R,R1 and J are independently chosen from alkyl, saturated or unsaturated,branched or linear, from 1 to 22 carbons, —H, —CH2OH, —CH2CH2OH,—C(Q)(Q′)(Q″) where Q,Q′, and Q″ are independently chosen from —H, —CH3,—CH2CH3, —CH2OH, L is chosen from —H, —CH3, —CH2CH3, —OH. n is 1 or 2, mis an integer from 1 to 6.

FIG. 125 teaches a series of mild zwitterionic surfactants, where A, Dand E are independently chosen from —H, —CH3, —CH2CH3, —CH2CH2CH3,—CH2OH, —CH2COOH, —CH2CH2COOH, —CH2CH(CH3)COOH, —CH2PO(OH)2. G is chosenfrom —H, —CH3, —CH2CH3, —OH. J is chosen from alkyl, alkenyl, alkynyl,branched or linear, —H, —(CH2CH2O)nH, —(CH2CH2CH2O)nH, —(CH2CH(CH3)O)nH,—(CH2C(CH3)2O)nH. R′ is chosen from, alkyl, alkenyl, alkynyl, branchedor linear. L, M, and Q are chosen from N or C. n is an integer greaterthan zero.

FIG. 126 teaches a series of mild zwitterionic surfactants based onsulfonate and phosphonate chemistries. A, D and E are indepently chosenfrom —H, —CH3, —CH2CH3, —CH2CH2CH3, —CH2OH, —CH2COOH, —CH2CH2COOH,—CH2CH(CH3)COOH, —CH2PO(OH)2. G is chosen from —H, —CH3, —CH2CH3, —OH. Jis chosen from alkyl, alkenyl, alkynyl, branched or linear, —H,—(CH2CH2O)nH, —(CH2CH2CH2O)nH, —(CH2CH(CH3)O)nH, —(CH2C(CH3)2O)nH. R′ ischosen from, alkyl, alkenyl, alkynyl, branched or linear. n is aninteger from 1 to 6. L, M, and Q are chosen from N or C.

FIG. 127 teaches sultaine buffers and surfactants where A, D and E areindependently chosen from —H, —CH3, —CH2CH3, —CH2CH2CH3, —CH2OH,—CH2COOH, —CH2CH2COOH, —CH2CH(CH3)COOH, —CH2PO(OH)2. J is chosen fromalkyl, alkenyl, alkynyl, branched or linear, —H, —(CH2CH2O)nH,—(CH2CH2CH2O)nH, —(CH2CH(CH3)O)nH, —(CH2C(CH3)2O)nH. R is chosen from—H, alkyl, alkenyl, alkynyl, branched or linear, saturated orunsaturated from 1 to 22 carbons. G, M, and L are chosen such that anyone can be Nitrogen, the others Carbon. n is 1 or 2, m is an integerfrom 1 to 6 inclusive.

FIG. 128 teaches an amino sugar zwitterionic buffer.

FIG. 129 teaches the synthesis of a range of amino esters and amidesthat are useful as anti-strips in asphalt and asphalt emulsifiers. A andD are independently chosen from —H, —CH3, —CH2CH3, —CH2CH2CH3, —CH2OH,—CH₂COOH, —CH₂CH₂COOH, —CH₂CH(CH₃)COOH, —CH₂PO(OH)₂. n is the generallyaccepted symbol for the repeating unit of a polymer, m is an integer,zero or greater. R and R1 are alkyl, saturated or unsaturated, linear orbranched, cyclic or acyclic from 1 to 22 carbons.

FIG. 130 teaches the synthesis of ether amino acid buffers. A, D and Eare independently chosen from —H, —CH3, —CH2CH3, —CH2CH2CH3, —CH2OR,—CH2COOR, —CH2CH2COOR, —CH2CH(CH3)COOR, —CH2PO(OH)2, —CH2CH2CN. G ischosen from —H, —OH, —CH3, or —CH2CH3, —CH2COOH. R is alkyl, linear,branched, saturated or unsaturated, cyclic or acyclic from 1-22 carbonsor —H.

FIG. 131 teaches the synthesis of aromatic ring containing miningcollectors.

Several drawings and illustrations have been presented to aid inunderstanding the invention. The scope of the present invention is notlimited to what is shown in the figures.

DETAILED DESCRIPTION OF THE INVENTION

Combining amines with monochloroacetic acid (MCA) or sodium vinylsulfonate (SVS) results in products are zwitterionic buffers that canbuffer in both acidic and basic pH conditions. A limited number aminesare currently used for this purpose, such as, tromethamine and ammonia.The reaction of amines, alcohols, and aminoalcohols with acrylonitrile(via the Michaels Addition), followed by reduction results in amines andpolyamines that have a broad buffering range. The further derivatizationof the amines and polyamines with MCA and SVS yields a further crop ofamine buffers with desirable properties. One skilled in the art willrecognize that MCA and sodium monochloroacetic acid (SMCA) can be usedinterchangeably.

The reaction of tromethamine as described above yields the products inFIG. 1. In step 1 in FIG. 1 where the acrylonitrile is added to theamine a branched structure wherein the addition of acrylonitrile resultsin a tertiary amine is shown. In reality, particularly when n is greaterthan 1, a mixture of products is obtained that is both tertiary andsecondary. For the invention disclosed herein, n may equal any integergreater than zero, including 1. Controlling the reaction temperature,pressure and agitation will allow the mixture to be predominatelysecondary (such as when m=n) or tertiary amine, m can be any integerless than or equal n. Furthermore, this selection can take place inadding acrylonitrile to the amine that results, allowing a progressivelymore branched product. It is within the scope of the invention disclosedherein to include these additional types of products and theirsubsequent derivatives described herein.

With regard to the reaction of the polyamine resulting from the secondstep in FIG. 1. FIG. 1 shows the addition of only one mole of SVS orMCA, it is known in the art, that a second mole may be added to obtain aproduct with a second zwitterionic group. Furthermore, in the case wherethe product has repeated additions of acrylonitrile and reduction to theamines, the branched products may have many more zwitterionic groups.Also, it is to be noted that, while the sulfonates are shown as sodiumsalts, other salts and the free acids (non-salted form) are also withinthe scope of this invention.

Other amines that would make excellent starting materials in place oftromethamine are 2-amino-2-methyl-1-propanol, 2-amino-1-butanol,2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1,3-propanediol, anddihydroxymethylaminomethane.

Additionally, fatty amines, such as lauryl amine, coco amine, tallowamine, and oleoyl amine, and fatty ether amines, such asbis-(2-hydroxyethyl) isodecyloxypropylamine, when reacted with SVSproduce mild surfactants that find utility where zwitterionicsurfactants are desired, including personal care.

Other amines that are shown in FIG. 2 are produced via a similar seriesof reactions, except that FIG. 2 includes zwitterionic buffers from theamine 2-amino-2-methyl-1-propanol, as well as the polyamines derivedfrom the reaction with acrylonitrile and the subsequent derivativesdescribed above. Other amines can be utilized in addition to2-amino-2-methyl-1-propanol to obtain excellent buffers are2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1,3-propanediol, and dihydroxymethylaminomethane.Reaction conditions could be created such that the alcohol groups on theamines listed above could be reacted with acrylonitrile as well, andthen reduced to the amines and, if desired, reacted with SVS or MCA toimpart zwitterionic character.

Polyamines with good properties for use in biological fermentations,purifications, storage and general handling can also be produced throughthe reaction of nitroalcohols and acrylonitrile, followed by reduction.Additional derivatization with SVS or MCA will result in zwitterionicbuffers with a very large buffering range and capacity.

FIG. 3 shows the reaction of 2-methyl-2-nitro-1-propanol withacrylonitrile and its derivatives.

FIG. 4 shows the reaction of 2-nitro-2-ethyl-1,3-propanediol withacrylonitrile and its derivatives where x, y, and n are all integerswhere x and y are chosen independently, such that x+y=n and n is greaterthan zero.

FIG. 5 shows the reaction of 2-nitro-2-methyl-1,3-propanediol withacrylonitrile and its derivatives where x, y, and n are all integerswhere x and y are chosen independently, such that x+y=n and n is greaterthan zero.

FIG. 6 shows the reaction of tris(hydroxymethyl)nitromethane withacrylonitrile and its derivatives where x, y, z, and n are all integerswhere x, y and z are chosen independently, such that x+y+z=n and n isgreater than zero.

FIG. 7 shows the reaction of 2-nitro-1,3-propanediol with acrylonitrileand its derivatives where x, y, and n are all integers where x and y arechosen independently, such that x+y=n and n is greater than zero.

FIG. 8 shows the reaction of 2-nitro-1-butanol with acrylonitrile andits derivatives.

FIGS. 2 through 8 are subject to the same clarifications as FIG. 1 withregard to the cyanoethylation and the formation of a more linear orbranched structure as well as the addition of SVS or MCA in molarequivalents of primary amine groups or less than molar equivalents ofprimary amine groups present.

The buffers described thus far may also be ethoxylated, propoxylated, orbutoxylated to modify their properties. Ethoxylation will tend to impartsurfactancy to the resulting product. Propoxylation will addsurfactancy, but also reduce the water solubility. This is useful inemulsion breaking and reverse emulsion breaking, this will also findutility in breaking up and dissolving biofilms. This is also desired inoil-field applications. Butoxylation will similarly shift the HLB to thehydrophobic. Combinations of ethoxylation, propoxylation, andbutoxylation can be tailored to specific emulsion and reverse emulsionforming and breaking requirements. FIG. 9 shows alkoxylation ofaminomethylpropanol. The direct 2 mole ethoxylation of2-amino-2-methyl-1-propanol with 2 moles of ethylene oxide, as shown inFIG. 9 produces an excellent biological buffer with less chelation than2-amino-2-methyl-1-propanol. The reaction of 2-amino-2-methyl-1-propanolwith propylene oxide or butylene oxide yields a similarly less chelatingproduct, as does the reaction with diethylene glycol. The reactionproduct of 2-amino-2-methyl-1-propanol with 1 mole of diethylene glycolas shown in FIG. 9 produces an ideal amine for gas scrubbing of H₂S.This product is particularly useful because it does not bind to carbondioxide and carbon monoxide in any appreciable amount. Thus making itideal for tail gas scrubbing and maximizing the capacity of sulfurplants in refineries. Similar performance is seen with the reaction ofthe following amines 2-amino-1-butanol,2-amino-2-methyl-1,3-propanediol, 2-amino-2-ethyl-1,3-propanediol,tris(hydroxylmethyl)aminomethane, and 2-amino-1,3-propanediol.

The buffers described herein also make excellent starting materials forsurfactants. FIG. 10 shows the synthesis of 2 very mild, high foaming,surfactants that are well suited for personal care applications wereirritation is problematic, such as baby shampoo and face cleansers.Similar results are seen when 2-amino-1-butanol,2-amino-2-methyl-1,3-propanediol, 2-amino-2-ethyl-1,3-propanediol,tris(hydroxylmethyl)aminomethane, and 2-amino-1,3-propanediol are usedas the starting material in place of 2-amino-2-methyl-1-propanol.

Polyamines with good properties for use in biological fermentations,purifications, storage and general handling can also be produced throughthe reaction of nitroalkanes and acrylonitrile, followed by reduction.Additional derivatization with SVS or MCA will result in zwitterionicbuffers with a very large buffering range and capacity. FIG. 11 showsthe synthesis of a series of buffers with 2-nitropropane as the startingmaterial. FIG. 12 shows the synthesis of a series of buffers with1-nitropropane as a starting material where n and m are integers wherem+n is greater than zero and n is greater than or equal to m. Branchingcan be imparted on the buffers described in FIGS. 11 through 14 for thepolyamines that have greater than 3 amine groups by reducing theresulting nitrile or polynitrile to the polyamine and then reacting withmore acrylonitrile and then reducing the resulting nitrile groups toamine groups. This can be done repeatedly. As in FIG. 1, conditions canbe chosen such that a more branched product results. A more linearproduct is produced by simply adding all the acrylonitrile in one step,and then reducing the resulting polynitrile to the polyamine. For FIGS.12 through 14, the zwitterionic products can be made by adding MCA orSVS as shown in FIGS. 2 through 8.

FIG. 13 shows the synthesis of a series of buffers with nitroethane as astarting material where n and m are integers where m+n is greater thanzero and n is greater than or equal to m. FIG. 14 shows the synthesis ofa series of buffers with nitromethane as a starting material where x, y,z and n are integers and x+y+z=n and n is greater than zero.

Several descriptions and illustrations have been presented to enhanceunderstanding of the present invention. One skilled in the art will knowthat numerous changes and variations are possible without departing fromthe spirit of the invention. Each of these changes and variations arewithin the scope of the present invention.

Another embodiment of the present invention is the synthesis ofzwitterionic buffers with vinyl acids. FIG. 15 shows the synthesis of afamily of zwitterionic buffers based on members of the acrylic acidfamily. However, other vinyl acids may be used. Vinyl acids such asacrylic, 3-butenoic acid, 4-pentenoic acid, and other carboxcylic acidswith a double bond at the terminus. Carboxcylic acids with a triple bondat the terminus also can be utilized, similarly, an acid where themultiple bond is not at the terminus, such as hex-4-enoic acid, can alsobe utilized. However, due to the reduced commercial availability of suchcompounds, the preferred embodiment is the vinyl acid with a double bondat the terminus. One very large benefit of utilizing vinyl acids to makezwitterionic buffers is that the product does not need to be ionexchanged to produce a non-ionized form. In the market, both ionized, orsometimes called salted, and non-ionized forms sometimes called freeacid or free base, are required. In situations where ionic strength mustbe very closely controlled, the non-ionized forms are more popular. Forcases where increased water solubility and ease of solution are desired,the salted forms are preferred. It is understood to one skilled in theart, the present invention covers both the ionized and non-ionized formsof the buffers disclosed herein.

Another embodiment of the present invention is the sulfonatezwitterionic buffers derived from the reaction of an amine with anepichlorohydrin and sodium bisulfate condensate as described in FIG. 16.It is understood by one skilled in the art that other sulfate salts canbe utilized to arrive at the desired molecular structure and is includedin the present invention. FIGS. 17 through 25 teach the flexibility ofthe present invention to synthesize a series of a amine sulfonate oramino acid zwitterionic buffers from nitroalcohols or alkanolamines toproduce zwitterionic buffers that have primary amino functionality orsecondary amino functionality. In cases where there are more than onereactive group, amine, alcohol, or a combination, multiple sulfonategroups or acid groups can be reacted by adding more than one equivalentof the vinyl acid or the oxirane containing sulfonate.

Another embodiment of the current invention is to make zwitterionicbuffers with cylcoamines as the starting material. The cycloaminesresult in a tertiary amino group that is less chelating and interferesless in biological functions. FIG. 26 shows the reaction of morpholinewith a vinyl acid and morpholine with the oxirane sulfonate. FIG. 27shows similar products, but utilizing hydroxyethyl piperazine. FIG. 28shows the use of diamines as starting materials by using piperazine asthe starting material. This is a good example of a synthesis ofpolyzwittterionic buffers as discussed earlier. FIG. 29 shows the use ofethylene amines to make zwitterionic buffers through reaction with vinylacids or oxirane sulfonates. One skilled in the art will recognize thatsimilar compounds can be made by using ethylene amines, such asmonoethanolamine and the higher homologs, such as diethylenetriamine andis part of the invention disclosed herein.

Another embodiment of the current invention is the synthesis ofzwitterionic amines that have primary, secondary, tertiary, andquaternary amine functionality. FIG. 30 shows this via oxirane sulfonateand amines. One skilled in the art will recognize that any primary,secondary, or tertiary amine can be used in place of the methyamines inFIG. 30. While not shown in the figure, one skilled in the art willrecognize that the resulting amines can be reacted further with vinylacids, monochloroacetic acid, sodium vinyl sulfonate, or an oxiranesulfonate to further add acidic character to the zwitterionic buffer.

Another embodiment of the current invention is the synthesis of mildsurfactants from nitroalcohols. FIGS. 31 through 33 teach the synthesisof these mild surfactants. Lower molecular weight acids produce lowerfoaming mild surfactants, whereas higher molecular weight carboxcylicacids yield higher foam. Lauric acid is the preferred embodiment for ahigh foaming, mild surfact. Coconut fatty acid performs similarly, butat a lower cost. A good surfactant with low foam can be made usingoctanoic acid as the carboxcylic acid.

Another embodiment of the current invention is the synthesis ofpolyamines from nitroalcohols. FIGS. 34 and 35 teach the synthesis ofdiamines from nitroalcohols. FIG. 34 shows the synthesis with severalhydroxyl groups present. It is understood by one skilled in the art thatadditional amino groups can be added by reacting more than oneequivalent of epichlorohydrin to the nitroalcohol, up to the number ofhydroxyl groups, and then reacting the same number of equivalents ofamine to the oxirane containing amine. In the case where thenitroalcohol is reduced to the amino alcohol in the beginning, theaddition of base, such as caustic, to the amino alcohol will assist inthe reaction of the epichlorohydrin with the hydroxyl groups. Withoutthe base, the epichlorohydrin will preferably react with the amine asoutlined in the 1 equivelent addition depicted in FIG. 34 and FIG. 35.FIG. 36 demonstrates that tertiary amines can be used to makezwitterionic buffers with quaternary amine functionality from tertiaryamines. While not explicitly shown, any other tertiary amine can be usedas the starting material and is part of the invention described herein.FIG. 37 and FIG. 38 demonstrate that diamines can be made fromnitroalcohols by reacting sequentially the nitroalcohol withepichlorohydrin and then the second equivalent of the nitroalcohol,followed by reduction. Also taught is that a reduction step can takeplace in the beginning to yield a diamine with two secondary aminogroups. It is understood by one skilled in the art that thenitroalcohols or alkanolamines do not need to be symmetric, but othersmay be used in the synthesis of the diamine and is part of the inventiondisclosed herein.

FIG. 42 shows the synthesis of zwitterionic biological buffers fromamino alcohols and itaconic acid. These buffers have two acid groups andincreased buffering in the acidic range of pH 3-6. FIGS. 43 and 44 showthe synthesis of zwitterionic buffers with primary amine groups. Thesebuffers are preferred in applications such as personal care wheresecondary amines are seen as undesirable. The nitro diacids of FIG. 44also have great utility as chemical intermediates when synthesizingbioactive molecules.

FIG. 45 shows the synthesis of a family of zwitterionic buffers fromitaconic acid. The buffers in FIG. 45 are not limited to amino alcoholsas starting materials and provide a wide range of molecular size andsolubilities.

FIG. 46 shows the synthesis of a family of amphoteric surfactants. Thesesurfactants are preferred for there mildness, ability to perform in hardwater conditions and persistent lather when in the fatty tail isapproximately 10-12 carbons in length. The R group in FIG. 46 is toencompass the fatty acid family of carbon chain lengths, generally fromabout 6 to about 22 carbons. In the specific cases illustrated of lauricamine and lauric dimethyl amine reacted with itaconic acid, it isunderstood by one in the art that any chain length amine can be used andis in within the scope of the invention herein. Particularly, but notlimited to the fatty amines (carbon lengths of about 6 to about 22carbons, branched and linear, saturated and unsaturated), isopropylamine and butyl amine. The lower carbon chain lengths produce lowfoaming hard surface cleaners, while the carbon chains of about 8 to 10tend to produce the most foam. Higher chain lengths find utility asmineral collectors in floatation processes such as those employed iniron and potash mining.

FIG. 47 shows the synthesis of nitro acids from nitroparaffins. Asstated early, these are very flexible intermediates, particularly whensynthesizing bioactive molecules. Reduction of the nitro acids, as shownin FIG. 48 produces zwitterionic buffers with primary amine character.In the case of nitroparaffins that have more than one hydrogen bound tothe nitro bound carbon, more than one addition of the itaconic acid canoccur. The substitution can occur up to the number of hydrogen atomsbound to the nitro bound carbon.

FIG. 49 shows the synthesis of zwitterionic buffers from4-aminopyridine, FIG. 50 shows using the less stable ketimineconformation as the starting material. FIG. 51 shows the synthesis ofsultaine type buffers from 4-aminopyridine. Additional buffers can bemade by propoxylating and butoxylating 4-aminopyridine. The ethoxylatingand propoxylating will reduce the water solubility and reduce thebioavailability. This is one method of extending the time a material isbioavailable by making it available slowly, particularly if the moleculeis metabolized. Additionally, a triamine can be made by reacting2-aminopyridine with arcrylonitrile and reducing it to the triamine, orreacting with allylamine to keep the aromatic nature of the six memberedring. The resulting buffers are excellent buffers in their own right,but also have great promise in treatment of multiple sclerosis, andother conditions that can benefit from calcium or other cationinhibition. The anionic components, in particular, are all groups thatcan chelate cations.

FIG. 52 outlines the synthesis of taurine derived zwitterionic buffers.These molecules, along with the products in FIG. 53, homotaurine derivedzwitterionic buffers, are expected to find great utility in thepurification of proteins and in cell culture media. FIG. 54 shows thesynthesis of a series of zwitterionic buffers derived from asparticacid. These compounds are expected to be very useful in electrophoresisgels as they have a unique charge density and size profile. The sultainederivatives in FIG. 55 and FIG. 56 are expected to find great utility incell culture media and in purification due to their zwitterionic natureand pKa range. The zwitterionic buffers of FIG. 57 are expected to beprimarily useful in cell culture media. The buffers of FIG. 58 and FIG.59 are ideally suited for use in electrophoresis gels and in isoelectricfocusing. FIG. 60, FIG. 61 and FIG. 62 show the synthesis ofzwitterionic amidoamine buffers for use cell culture media andpurification.

FIG. 63 shows the synthesis of zwitterionic buffers that are expected tobe useful in the treatment of multiple sclerosis (MS) and spinal cordinjury by blocking potassium channels. The increased hydrogen bondingavailable through the sulfonate group is expected to enhance theefficacy over the traditional 4-aminopyridine therapy. While the figureshows only two compounds, one skilled in the art will recognize that anyof the amino acid taurates, including, but not limted to those disclosedherein, particularly those of FIGS. 52, 53, 54, and 57. FIGS. 64 and 65show the synthesis of a further class of amidoamine buffers that areexpected to be effective therapies for MS and spinal cord injury due tothe pKa and hydrogen bonding. FIGS. 66-68 shows the synthesis of a classof compounds that are excellent amidoamine buffers, particularly usefulfor electrophoresis and protein focusing. These are also expected to beexcellent therapies for MS and spinal cord injury through potassiumchannel blocking. The more hydrogen bonding variants are expected tohave greater efficacy. FIG. 69 shows the synthesis of a further class ofamidomine buffers that are also expected to have utility as MS or spinalcord injury therapies. One skilled in the art will recognize that theamino acids used are not limited to those presented but any amino acidcan be utilized and are within the scope of the present invention. Inparticular, the analogs based on methacrylic and other vinyl acids asthe amino acid reacted with 4-aminopyridine are within the scope of thepresent invention, similar to the analogs presented in FIG. 15 wheretromethamine is reacted with various acids to form a family of aminoacids. FIGS. 70-72 teach a family of amidoamine buffers. FIG. 73 showsthat any of the amidoamines presented herein, may be reduced to theaminoalcohol by reacting with hydrogen in the presence of a catalyst,such as raney nickel or raney cobalt, as well as reduced to the diamineby treatment with lithium aluminum hydride or similarly strong reducingagent.

As outlined earlier, one skilled in the art will recognize that theresulting amines can be reacted further with vinyl acids,monochloroacetic acid, sodium vinyl sulfonate, or an oxirane sulfonateto further add acidic character to the zwitterionic buffer. One skilledin the art will recognize that the salts and free acids and free basesof the compounds taught herein are within the scope of the invention.Additionally, to adjust the water solubility, it is useful to alkoxylateof the buffers taught herein, particularly with ethylene oxide,propylene oxide or butylenes oxide or a combination of alkoxylatingagents in any amount or ratio to reach the desired result. The resultingalkoxylates will in some cases produce surfactants. Another way to makemild surfactants from the buffers taught is to esterify. FIGS. 74 and 75show the esterification of the mono- and di-acid functionalzwitterionics. It is understood by one skilled in the art that all thezwitterionics taught herein may undergo this reaction in a similarfashion to those explicitly shown. For example, the FIGS. 74 and 75 donot explicitly show the esterification of the products of FIG. 26, butit is understood that the esterification is similar enough to berecognized by one skilled in the art. The 4-aminopyridine derivedzwitterionic buffers benefit from esterification in adjusting thebioavailability and water solubility, much as they do from alkoxylation,to improve their efficacy and reduce side effects when used as a therapyfor MS, Alzheimer's disease, or other medical use.

The primary amines that are the basis for the zwitterionic buffers, mayundergo disubstitution to form diacid functional buffers as shown inFIG. 76. These may be mono- or diesterified just as the itaconic acidbased buffers in FIG. 75. FIG. 77 expands on the amidoamines that can besynthesized from the zwitterionic buffers. The amidoamine formation mayalso be carried out by diamines to create dimmers, or with the secondarydiamines, such as coco diamine or tallow diamine to produce surfactantsthat act as corrosion and scale inhibitors.

FIG. 78 shows the synthesis of a variety of 4-aminopyridine derivativesthat are useful buffers. The varying amine strength and water solubilitygive them unique properties.

FIG. 79 shows the condensation polymerization of the hydroxyl functionalzwitterionic buffers. As shown, linear polyesters or polyesterprepolymers are produced. By using the buffers with varying hydroxylnumbers, a hydroxyl functional polymer results. When used as aprepolymer, greater cross-linking can be introduced when incorporatedinto a polyurea, polyurethane, or polyether. If condensed with theitaconic based buffers, such as those in FIG. 42, or other polyacidfunctional monomers or prepolymers, a 3 dimensional polyester polymermatrix can be achieved.

FIG. 80 further clarifies the ability to make diamines from the amidestaught herein. In FIG. 80, where G is —OH, it can either remain intactwhen done under milder reduction conditions, or be converted to —H whenharsher conditions, such as when LAH is used. The most useful of theseamidoamines and diamines is expected to be those whereA=D=E=M=J=L═—CH₂OH.

FIGS. 81, 82, 83 and 84 demonstrate how the sulfonate buffers can beconverted to sulfonamides. Sulfonamides have a wide range of knownbiological activity and these sulfonamides are expected to haveincreased antimicrobial properties versus their related sulfonates orcarboxcylic acid functional zwitterionics. It is well known in the artthat sulfonamides can be reduced under mild conditions to thesuflonimides, which are within the scope of the invention disclosedherein.

FIG. 85 shows the synthesis of quaternary amine salts. These productsare particularly useful in diagnostic kits for condution, as well asthere antimicrobial properties. The case where A═—CH₂OH andD=E═R═R′═—CH₃ is the most useful of this class, but the otherpermutations are useful when the water solubility needs to be increasedor decreased.

FIGS. 86 and 87 teach the synthesis of sulfonate esters from thezwitterionic buffers. These esters allow for changing the watersolubility, while maintaining buffering capacity. FIGS. 88 and 89 teachthe synthesis of zwitterionic buffers with primary amino functionality.Again, the 4-aminopyridine moiety containing buffers are promisingtargets for therapies to treat MS and potentially Alzheimer's disease orother diseases that involve demyelination or other myelin anomalies.

FIG. 90 expands on the quaternary amine salts shown in FIG. 85.

FIGS. 91 and 92 show the synthesis of buffers with adjusted HLB by usinghydroxyesters of acrylic acids. In FIG. 91, an example of adisubstituted amine is shown in the second line. This applies for allthe amine and acrylate pairs which are within the scope of the presentinvention. FIG. 91, in addition to showing the hydroxyester acrylateswhich can be made through acid catylized esterification of the acrylicacid, also show an alkoxylated acrylate. The alkoxylated acrylate can beprepared through acid catalyzed alkoxylation utilizing ethylene oxide,propylene oxide, butylene oxide or any other alkoxylate. The reactionproduct is a buffer that possesses a wide range of water solubilities.FIG. 91 includes this process.

FIG. 93 teaches the synthesis of phosphonates based on aminoalcohols andamino acids, as well as those derived from 4-Aminopyridine. Thesephosphonates are excellent buffers in their own right, but have otherbenefits. The phosphonates have a higher solubility profile when saltedwith divalent cations, such as, calcium, magnesium and zinc. This alsoresults in the molecules being excellent chelants and scale inhibitors.In addition, these phosphonates are expected to be quite biologicallyactive. The amino acid starting materials in FIG. 93 exhibit fungalresistance as well as resistance moss, mold and some bacteria. The4-Aminopyridine derivatives are biologically active as treatments for MSand other autoimmune diseases, such as rheumatoid arthritis, andconditions effected by abnormal myelination. The phosphonates areexpected to extend this efficacy further. In addition, the phosphonates,of the amino acids in particular, are expected to be excellentherbicides.

The phosphamides of FIG. 94 show great promise as insecticides andinsecticide precursors. These phophamides also show promise aschemotherapy agents for treatment of cancers. It is believed that thephosphamides taught are useful therapies for autoimmune diseases bysuppressing the immune response to various antigens. FIG. 95 teaches thesynthesis of zwitterionic sulfonates based on monochloroacetic acid.FIG. 96 teaches an enzyme inhibitor. FIG. 97 through FIG. 99 teach thesynthesis of diacid buffers. These buffers, while useful as buffers alsopossess unique biological properties, including enzyme inhibition. Thusmaking these very useful tools in agriculture, diagnostics, andbiotechnology. It is understood by one skilled in the art that the aminoacid starting materials could be substituted for their esters oralkoxylates, such as in FIGS. 74, 86, 91, 92, thus giving the analogousproducts.

FIG. 100 outlines a family of products that are useful buffers that areprimarily liquid and distillable. These products also have widerapplications, specifically in removal H₂S from both refinery processesas well as gas and liquid petroleum, products. The reduction of thecarbonyl produces compounds that are more stable to the harsh conditionsseen in oil and gas recovery and refinery processes. The final moleculeat the bottom of FIG. 104 is a hindered amine that has fewerinteractions than the primary amine with proteins, improving yield whenused to purify proteins. It is a suitable H₂S treating amine as well.Lines 2, 4, and 6 of FIG. 100 are present simply to underscore the factthese amines used as precursors may be mono or disubstitued, as madeclear in other sections. This is true for all the primary amine startingmaterials and the resulting products and the downstream derivatives thatresult are included within the scope of this invention. FIG. 101continues to teach the reduction of the zwitterionic buffers and theiresters to alcohols and ethers. For the sulfonic acid zwitterions, if thereduction is allowed to run longer or is run under stronger reducingconditions, such as with LAH, the sulfonic acid groups will be convertedto thiols. These thiols are also within the scope of the presentinvention.

FIG. 102 teaches the synthesis of a range of zwitterionic buffers basedon dopamine. These products, and there derivatives are excellent buffersin their own right, but also posses bioactivity, including fungalresistance. FIG. 103 includes sulfonamides that are particularly fungalresistant, as are the zwitterionic buffers taught. FIG. 104 primarilyteaches the synthesis of dopamine based zwitterionic buffers and theiresters. The esters expand the usefulness of the product by resulting inmore hindered buffers so that there are less interactions with proteinsthat can destabilize their tertiary structure. FIG. 105 teaches thesynthesis of sulfonamide and disulfonamide buffers based on thezwitterionic buffers previously taught. In addition to their buffercapability and utility in protein fermentation and purification, thesulfonamide buffers, particularly those based on 4-aminopyridine anddopamine, are expected to have use as therapeutic agents in areas wherefungal infection is part of the condition.

FIG. 106 demonstrates again the mono or disubtitutions that can takeplace with primary amines. Both species and there analog derivativesthat are taught in this application are within the scope of the presentinvention. The sulfonic acid buffers may also be synthesized as diacidsanalogous to the carboxcylic acid diacid analogs in lines 1 and 2 ofFIG. 106. They are not explicitly shown because it is obvious to oneskilled in the art that these molecules are part of the invention.

FIGS. 107 through 115 and FIG. 120 teach the synthesis of a new class ofamines and aminoalcohols, as well as a range of derivatives that aresuitable as buffers, monomers antimicrobials, and dispersants. Taughtare secondary amino acids based on monochloroacetic acid and acrylicacid type monomers and their esters for both classes, sulfonates,phosphonates, alkoxylates, and polyamines based on acrylonitrile. In thecases where A and/or D are —CH₂CH₂CN, subsequent reductions will yieldprimary amines, that can either be used directly, or further derivatizedas other amines in this invention have been, into amides, alkoxylates,reacted with MCA, acrylic acid and its variants, made into phosphonates,and made into sulfonates. While not shown in the figures in every case,the esters (standard esters, phosphate esters, phosphonate esters, andsulfonate esters) of these compounds that result from the reaction ofalcohols or polyols are also within the scope of this invention, forlinear, branched, saturated or unsaturated alcohols, including polyolssuch as, but not limited to, EG, PG, BG and polymers or blockco-polymers. These derivatives have been adequately within this patentapplication such that they are included within the scope of thisinvention.

While in the Figures, mainly the monosubstitution on the primary amineis shown for each type of derivative, it is part of this invention toinclude the disubstitution, analogous to what is shown in FIG. 76 andsimilarly throughout this patent application. It is worth pointing outthat when reacting acrylonitrile with the nitroalcohols, The secondaryalcohol reacts less quickly than the primary alcohol, when present, whenA and/or D include a primary alcohol group, as well as the primaryalcohol in all molecules in FIG. 109 where the amine starting materialfor the derivatives contains a primary alcohol. The reaction proceedsanalogous to the secondary alcohol shown, as does the reduction, ifpursued. An excess of acrylonitrile reacts both the primary andsecondary alcohols and at even greater levels, forms nitrile polymer.The primary alcohol groups will also undergo monosubstitutedalkoxylation, but at a slower rate than the amine, Less reactiveconditions, such as lower temperatures can limit the alkoxylation to theamine. The alkoxylation of the alcohol groups is also part of theinvention described.

In the case of the sulfonates, SVS is the only reactant shown, however,the analogous reaction with propane sultone is included as part of thisinvention. The result, as taught by analogy earlier in this patentapplication, is an additional carbon between the reactive amine and the—SO₃H group.

FIG. 110 teaches the synthesis of primary diamines from gluteraldehydeand nitro compounds. The figure focuses on the monosubtitution of bothof the primary amine groups. However, the invention includes themonosubstitution of just one amine, the disubstitution of both amines,and the disubstitution of one amine and monosubstitution of the other.Further, the invention includes the derivatives where one type ofderivative is made on one amine, and another of the described derivativetypes is made on the other. Likewise, as shown in FIG. 93, thederivations can vary on the individual amine and still be within thescope of this invention. FIG. 111 is a continuation of FIG. 110 in thatit teaches more derivatives of the gluteraldehyde based diamines anddinitro compounds. Specifically, alkoxylation and acrylonitrilederivatives.

FIG. 112 teaches the synthesis of a group of aminoalcohols based onglucose. While glucose is taught explicitly in this Figure, all aldehydeterminated sugars can be treated the same way as glucose to yield theanalogous amines. Other aldehyde terminated sugars included in thisinvention, but not limited to are allose, altrose, mannose, gulose,arabinose, xylose, fucose, idose, galactose, talose, ribose, arabinose,xylose, lyxose, erythrose, threose, glyceraldehyde, glycolaldehyde andthe related lactic aldehyde. In addition to sugars, flavoring aldehydesand fragrance aldehydes, such as, but not limited to, vanalin,cinnamaldehyde (including butyl and amyl), anisic, 2,4-heptanedienal,isovaleraldehyde, and citral, as well as furfural may undergo this sametransformation to make these novel aminoalcohols and their derivatives.It is worth noting that stereochemistry has no effect on this reaction,and therefore all stereo conformers are within the scope of thisinvention. Where a chiral center is introduced through the formation ofthe nitroalcohol, the results are racemic, and no stereochemistry inconveyed, nor implied in the structures presented. FIG. 119 expands theinvention to make surfactants by reacting glucose, or other aldehydes oraldehyde sugars with the nitro compounds of FIG. 107 and FIG. 120. Theinvention is not limited to the surfactants from the sugar aldehydesalone, but may be reacted with any of the aldehydes disclosed in thisinvention, as are the similar derivatives, such as the zwitterionics andphosphonates, which are also taught and within the scope of theinvention. The zwitterionic derivatives make very mild, high foamingsurfactants that also hold promise as mineral collectors in mining, suchas iron ore and other minerals. If D is —H, then a second substitutionof the E containing hydroxyl moiety can be achieved, leading to theanalogous surfactant with a generally more hydrophobic character.Naturally, these may be reacted with acrylonitrile and reduced to aminesor alkoxylated analogously to the glucose or aldehyde sugaraminoalcohols in FIG. 113. As in earlier forms, it is worth pointing outthat the zwitterionic surfactants may be mon- or disubstituted at theamine with the acidic functionality. FIG. 113 expands on FIG. 112 byteaching the acrylonitrile and alkoxylate derivatives. For thealkoxylation, the reaction can be significantly isolated to the primaryamine group is shown in the first line, however, more aggressivereaction conditions will cause the hydroxyl groups to undergoalkoxylation as well. Leading to a mixture of products. Additionally, itis common among alkoxylators to block coploymerize by reacting with onealkoxylating agent, such as EO, then another, such as PO or BO andrepeat the process to achieve the desired HLB. This results in a widerange of products as alkoxylations of this type are not precise and donot yield a single product. This block copolymerization is within thescope of this invention for this and all alkoxylations taught. Further,the primary amine may be retained by performing the alkoxylation on thenitro compound that results in the first line of FIG. 112. After thealkoxylation is complete, the nitro group can be retained, or reduced tothe primary amine. Similarly, the reaction with acrylonitrile on theprimary amine forming the diamine (which can be derivatized by any ofthe methods disclosed and included as part of this invention) can alsooccur on the alcohol groups under more aggressive conditions. Similarly,by reacting the nitro compound with acrylonitrile, the hydroxyls willreact with the acrylonitrile, more equivelents of acrylonitrile willresult in more hydroxyls being substituted, which can be isolated andused as a reactive intermediate, or reduced to the polyamine. Thiscourse produces a high yield of primary amines, verses the secondary andprimary amine groups that result from reacting the acrylonitrile withthe primary amine. Again, these polyamines undergo the samederivitations as taught in this invention for the other classes ofamines taught. FIG. 114 teaches the synthesis of and derivatives ofbenzaldehyde and nitro compound amines. Again, the alkoxylation can bedone on the amine, and largely isolated to the amine, or under moreaggressive conditions, on the hydroxyls as well. If alkoxylating thenitro compound, the alkoxylation will be isolated to the alcohol groupspresent. Reduction of the alkoxylated nitro compound will yield aprimary amine. Due to the chiral nature of many of these molecules andtheir derivation from natural molecules, in addition to being excellentbuffers, they are expected to be useful in pharmaceutical and other lifescience applications as part of drug delivery systems, and some, astherapeutic agents themselves.

FIG. 115 is a continuation of FIG. 114 and teaches the acrylonitrilederivatives. As is the case in previous cases, the acrylonitrileaddition can be isolated to the primary amine, mono (shown) ordisubstituted, or under more aggressive conditions, also react with anyhydroxyls present. The resulting nitrile compounds can readily bereduced to their amine counterparts. Reacting the nitro compound, willresult in the hydroxyls being substituted, which can then be reduced,along with the nitro group, which will produce in high yield primaryamines and minimal secondary amine formation. These amines can thenundergo all the derivatives taught in this invention utilizing theaminoalcohols and are part of this invention.

FIGS. 116-117 teach the synthesis of dimmers, trimers and polymers whenat least two hydrogens are present on the nitro containing carbon, andhow polymers may be produced. When more than one hydrogen is present onthe carbon containing the nitro group, polymerizartion is always aconcern. However, controlling the addition order, rate and temperaturecan prevent polymer formation. Many of the methoxy containing productscan be made by reacting the remaining hydrogen(s) with formaldehydeprior to the reduction to the amine, but using the nitroalcohol ispreferred as it leads to much less polymer formation. Particularly incases where the reaction conditions can not be well controlled. Theamines and polyamines taught in the figures are able to undergo all thederivations taught and are part of this invention. Including, but notlimited to aminoacid products sulfonic acid products, phosphates,phosphonates, polyamines via acrylonitrile, and alkoxylation. FIG. 118teaches a novel route to primary amino acids of several types and theirnitro precursors. Again, monosubstitution is taught, but thesubstitution can by di- or tri if sufficient hydrogens are present inthe starting nitro compound.

A great deal has been said about the nature of the primary amines thatare starting materials for the invention may undergo mono ordisubstitution, as shown in FIG. 76. While much of the disclosurefocuses on the mono substituted species for clarity, the disubstitutedspecies for each class of molecule or derivative are fully part of thisdisclosure and their analogous derivatives that have been taught.Further, for all transformations taught, it is within the scope of thisinvention to include the monosubstituted derivative, then derivatizedwith another method taught, such as is shown in FIG. 93, line 3 wherethe amine starting material is the monosubstituted amino acid made withMCA, then the second substitution is made as a phosphonate.

FIGS. 121-123 expand on the buffers of 4-aminopyridine to include2-aminopyridine and 3-aminopyridine. FIG. 121 specifically introducesthe monomers and resulting dimers, oligamers, polymers, and copolymersof the monmers. By reacting the acrylate monomer with the aminopryidineunder acidic conditions, the ester is formed, while keeping the doublebond intact. The resulting monomer can be polymerized with other vinylgroup containing monomers, including, but not limited to vinyl chloride,acrylic acid and its esters and the substituted acrylic acids (such asmethacrlyic acid) and their esters, and ethylene to create amidopyridinefunctional polymers. In FIGS. 121-123, the carbonyl may be reduced awayby the use of lithium aluminum hydride, similar to row 3 in FIG. 100.Alternatively, the allyl alcohol, substituded allyl alcohol (such asmethallyl alcohol), or their esters may be substituted for the acrylicacid or substituted acrylic acid or their esters to reach the samemolecules. Yields tend to be less, and generally require a strippingstep to remove the unreacted components, but requires less capableequipment. This is true for the previous examples, such as FIG. 100, andthe other figures where LAH is shown to reduce the carbonyl of an acidor ester to yield the alcohol or ether. FIG. 124 teaches a series ofchannel blockers/regulators that are based on aminopyridines.Additionally, antibiotic properties are present in diaminopyridinesulfonamides. FIGS. 125-127 teach the synthesis of mild surfactants withbioactivity. FIG. 128 teaches the synthesis of an amino sugar that hasantiviral properties in addition to zwitterionic buffering. Thereduction in step two must be done with a mild reducing agent to preventthe reduction of the phosphonate while reducing the nitro to the amine.Commercially acceptable results are acheived with Fe powder.

FIG. 129 clarifies some of the FIG. 117 derivatives. The ester and amidederivatives that are present in FIG. 129 are shown as mono esters andmono amides, the esters can be made to the extent of the presence ofalcohol groups on the nitro alcohols. The esters and amides need not allhave the same alkyl groups. Sequential esterification or amidizationwith differing alkyl groups can be utilized to produce polyamides,polyesters, and amidoesters that have varying alkyl groups.

The esters can also be made if the amine groups have been derivatized totertiary amines as already shown in the previous figures, or as amides.The aminoalcohols or amino esters can similarly can be derivatized intoamides to the extent that primary amines exist. FIG. 129 only shows themono amide, but the polyamides are also part of the invention, includingthe specific case where nitroparaffins are reacted in molar equivalentsgreater than one to the one of the aldehydes, such as the case ofnitromethane shown in FIG. 117. The nitro alcohols and amino alcoholscan still be alkoxylated in the same manner as has been shown multipletimes in previous figures where the alkoxylating agent adds at thenon-tertiary amines or alcohol groups. The primary or secondary amines,as well as the free hydroxyl groups can made to react with acrylonitrileto form nitriles or polynitriles and either used as is, or the nitrilegroups reduced to amino groups with sponge metal catalysts and hydrogenor other reducing agents. The resulting polyamines are also useful oncealkoxylated. The amides of the diamines make excellent emulsifiers inasphalt emulsions, the polyamines are excellent anti-strips. By reactingwith formaldehyde and phosphorous acid as shown in previous figures,produces phosphonates that are excellent corrosion inhibitors. Thesederivatives that follow the established derivatization are part of theinvention.

FIG. 130 teaches the synthesis of ether aminoacid buffers that alter thewater solubility of the buffers and can also act as surfactants andantifungal compounds useful in a range of applications including paintsand coatings, agriculture and mining. FIG. 131 teaches the synthesis ofaromatic ring containing fatty nitro compounds and the amines andpolyamines that can be obtained from them. In the case where A and/or Dare —CH₂CH₂CN, when reduction steps occur, primarily to convert —NO₂groups to primary amines, the nitrile will also be reduced to thecorresponding primary amine. The addition of additional moles ofacrylonitrile can be extended beyond 2 moles and can be added one moleat a time, followed by reduction, to introduce linear polyamines, ormultiple moles at a time to create branched polyamines. Additional molesbeyond two are part of this invention. These products are usefulcollectors in mining in both direct or conventional floatation as wellas reverse flotation.

For all the molecules taught herein where a starting material is acarboxcylic acid, an aldehyde, or an acid chloride, the tall oil fattyacid analog, containing the five membered ring, is included, as are therosin acids analogs. Both generally included under the alkyl cyclicdesignation.

An additional use for the molecules taught herein is the use in printmedia to reduce bronzing, similar to that taught in U.S. patentapplication Ser. No. 12/248,323, which is incorporated by reference.Additionally, the bioactive nature of these molecules makes many of themantimicrobial in nature. The use of these molecules, particularly, butnot only, the carboxcylic acid functional molecules and there salts showthis property under a wide range of conditions. The use of the moleculesdisclosed in this invention are also known to exhibit synergisticantimicrobial properties when used in combination with other knownantimicrobials. The antimicrobials known to show synergy include, butare not limited to isothiazolinones, carbamates, formaldehydecondensates, formaldehyde donors, phenols, parabens, quaternary ammoniumcompounds, methylenes, metals and their organic salts, halogenatedorganics and inorganics, hexetidine, phthalates, sulfonamides and allother antimicrobials. In addition to the other uses for the inventiondescribed are as gas scrubbing amines for removal of acid gases, such asCO₂, H₂S, CO and other acidic gases from industrial processes. They canbe used alone, or in combination with other amines, solvents, and allother known means of removing acid gases. Further application of themolecules disclosed herein is the use as dispersants for minerals,pigments, chelation of cations, corrosion inhibition, and the preventionof scale formation. The molecules taught also have great potential asherbicides or adjuvents, particularly when used with other adjuvents,but also alone. Adjuvents that are expected to increase the efficacy,weather used alone or in combinations that may include othersurfactants, solvents, or coupling agents include alcohols, amines,ethyleneamines, alkoxylated amines, alkoxylated alcohols, ether amines,alkoxylated etheramines, taurates, sarcosinates, polyethylene glycol,polypropylene glycol, EO/PO block polymers and other non-ionicsurfactants, particularly the broad class of alkoxylates. It is alsoexpected that the molecules taught will be tolerated by glyphosatetolerant crops.

Furthermore, the zwitterionic buffers of this invention find use in theelectronics industry and other applications that require the precisecontrol of pH while keeping the ionic strength low, or requires that thecounter ion be larger than typical mineral acid or mineral base counterions as conjugate acids or bases. An example is the process of chemicalmechanical planarization used in the manufacture of semiconductorwafers. The presence of chlorine or sodium ions poison the n or p holesof the wafer, the use of the zwitterionic buffers here allow foreffective buffering and dispersion, while being large enough to beexcluded from the n and p holes of the wafer. This same set ofproperties that are present in the disclosed buffers is also beneficialin paints and coatings as the lack of mineral acids and bases asconjugate acids/conjugate bases reduces the corrosion potential andreduces or eliminates flash rusting of metal substrates. Additionalknown benefits include: bioactivity, bioresistance/fungal resistance,antimicrobial synergists, dispersion, surfactancy, prevention of printbronzing, emulsion stabilization, ion complex stabilization, crosslinking of guar and other hydroxyl functional polymers, bentonite andother clay surface passivation, acid gas or base sequestering(especially hydrogen sulfide). The molecules find use in therapies fordiseases and illnesses that target nerves, ion channels, myelin, andform amyloid plaques, as well as antivirals, and therapies forrheumatoid. The molecules are also useful in treating spinal cordinjuries by restoring some nerve function by potassium channel blocking.The molecules are also useful in agriculture as adjuvents andsurfactants with bioresistant properties that do not increase thebiodegradation potential of the final product, and polymer buildingblocks with asymmetric reactivity. The molecules taught also have theability to inhibit enzymes, such as 5-enolpyruvylshikimate 3-phosphatesynthase. The molecules described also have potential as insecticide andinsecticide precursors, and anti-cancer agents, and autoimmune diseasetherapies, particularly the phosphamides. The aminopyridines in additionto their use as an Alzheimer's therapy, a treatment for neurodiseases orinjuries that effect the myelin sheath, and Parkinson's disease, thesemolecules have shown promise in diabetes treatment of type I orneonatal, as well as pain treatments (local and general anesthetic),arrhythmia and angina treatments, and mucosal dryness.

The diacid buffers are very strong chelators, as are the monoacids.These molecules find utility anywhere strong chelants are valuable,including agriculture, oilfield, hydraulic fracturing, pharmaceuticalsand pharmaceutical delivery systems, waste removal, water treatment,personal care, paints and coatings, semiconductor manufacturing, andsurface treating. The changes in solubility that occur when complexedversus free zwitterion can be taken advantage of to adjust theavailability of the chelated species or the zwitterion, either bytiming, hydrophilic/hydrophobic, solids/liquids, liquids/gasses,solids/gasses. The solubility changes can also be taken advantage of toseparate ions from solution (gas or liquid) or assist in solvating ions.

Several descriptions and illustrations have been presented to enhanceunderstanding of the present invention. One skilled in the art will knowthat numerous changes and variations are possible without departing fromthe spirit of the invention. Each of these changes and variations arewithin the scope of the present invention.

I claim:
 1. The biological buffer of the following structure and itssalts:

where A and D are independently chosen from —H, —CH3, —CH2CH3,—CH2CH2CH3, —CH2OH, —CH2O(CH2CH2CH2NH)_(n)H, and where n and m areintegers greater than zero.
 2. The biological buffer and its salts ofclaim 1 wherein A=D=—CH3 and m=1.
 3. The biological buffer and its saltsof claim 1 wherein A=D=—CH2OH and m=1.
 4. The biological buffer and itssalts of claim 1 wherein A=D-CH2O(CH2CH2CH2N)_(n)H and n=m=1.
 5. Thebiological buffer and its salts of claim 1 wherein A=—CH2CH3,D=-CH2O(CH2CH2CH2N)_(n)H and n=m=1.
 6. The biological buffer and itssalts of claim 1 wherein A=-CH3, D=-CH2O(CH2CH2CH2N)_(n)H and n=m=1. 7.The biological buffer and its salts of claim 1 wherein A is —CH3 and Dis —CH2CH3.